Lithium Hydroxide → 6,7-Dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride

HRID 1620236Notes

Reaction equation

HRID 1620236 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2

Participants

6

Reactant 3

HCID 3939Lithium HydroxideHCID 681821763-(Chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochlorideHCID 178440211HCID 178440211, compound

Product 1

HCID 1784402266,7-Dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochlorideYield 11%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (116 mg, 0.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41062 (160 mg, 0.47 mmol) at RT followed by a 2 N aq. solution of LiOH (0.47 mL, 0.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 30 mg of 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride SLA 41064 as a yellow solid (31 mg, 11% yield).

Workup

  1. temperatureAfter cooling to RT
  2. washMeOH=9:1 (150 mL), washed with brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated at 40° C. under vacuum
  6. customPurification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3)
  7. customfollowed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)
  8. customprovided
  9. customafter evaporation, 30 mg of 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid
  10. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
  11. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL)
  12. stirringThe reaction mixture was stirred for 5 min at RT
  13. concentrationthen concentrated at 40° C. under vacuum

Sources & evidence

ORD record
ord-dbd12a55dabd4daf8dbfb2c402cb4a1d
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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